Process for separating tocopherol epimers



United States Patent 3,344,151 PROCESS FOR SEPARATING TOCOPHEROL EPIMERS Donald R. Nelan, Rochester, N.Y., assignor t0 Eastman Kodak Company, Rochester, N.Y., a corporation of New Jersey No Drawing. Filed July 2, 1965, Ser. No. 469,316 13 Claims. (Ci. 260-4456) This invention resides in the chemical arts. More particularly, it relates to that branch of organic chemistry having to do with tocopherols.

a-Tocopherol is a well-known compound which is represented by the following structural formula:

The carbon atoms at the 2, 4 and 8 positions are asymmetric. Consequently, a-tocopherol can exist in eight, different, optical isomer forms.

a-Tocopherol synthesized "by condensation of trimethylhydroquinone and natural phytol is a mixture of diastereoisomers. The mixture is racemic, giving in most solvents a specific rotation of zero, wherefore, this synthetic material has been designated as dl-a-tocopherol. (Naturally occurring a-tocopherol has been designated as d-a-tocopherol due to the small dextro rotation observed in most solvents.) This mixture consists of two diastereoisomers, or epimers, at a 50:50 weight ratio and they are identified herein as 2d,4d,8d-a-tocopherol (or the 2d epimer) and 2l,4d,8'd-m-tocopherol (or the 21 epimer). For convenience dl-a-tocopherol such as that made from tn'methylhydroquinone and natural phytol, which consists of these two epimers at a 50:50 weight ratio, is referred to herein as 2dl-u-tocopherol.

Before proceeding further it should be noted that diastereoisomers that differ in configuration at only one asymmetric center or carbon are sometimes called epimers. The term epimers originated in the physical chemistry of the sugars and was defined as sugars which diifered in configuration at one carbon atom, such as, for example, glucose and mannose. As employed herein epimer refers to a diastereoisomer that differs from another diastereoisomer at only one asymmetric carbon, and epimeric material refers to material consisting essentially of two diastereoisomers that are epimers.

a-Tocopherol and esters thereof have vitamin B activity. However, the vitamin E potency varies according to the optical isomer or isomers involved. This fact is reflected in the National Formulary, eleventh edition, on page 459, wherein these equivalents are given:

1 milligram of d-ot-tocopherol=l.49 International Units of Vitamin E 1 milligram of d1-utOCOph6IOl=1.1 International Units of Vitamin E 1 milligram of d-a-tocopherol acetate=1.36 International Units of Vitamin E 1 milligram of dl-u-tocopherol acetate=1.0 International Units of Vitamin E.

Thus, dl-a-tocopherol has only about 73.8% of the biological activity of an equal weight quantity of d-a-tocopherol While (ll-oc-tOCOPhfl'Yl acetate has only 73.5% of the biological activity of an equal quantity of d-a-tocopheryl acetate. The reason for these differences in biological activity is the presence of the l isomer in the synthetic material and the acetate ester thereof. In this regard it has been established that l-oz-lZOCOPhCIOl and its acetate ester have less biological activities than d-a-tocopherol and its acetate ester.

One problem, therefore, to which this invention provides a solution is that of separating the 2d epimer from the 21 epimer of 2dl-wtocopherol and esters thereof.

One solution to this problem is reported in the US. Patent No. 3,153,053, to Robeson and Nolan. It is disclosed in this patent that piperazine compounds selected from the group consisting of piperazine and C-methyl and C-ethyl substituted piperazines react with 6-chromanols in the absence of Water to form crystallizable complexes. The separation process described in this patent is based on the fact that at the temperature of crystallization more of the piperazine complex of one of the epimers is crystallized than the piperazine complex of the other of the epimers. However, the difierence in quantities crystallized is not as great as desired, with the result that the yields in each crystallization step are not as large as is desired and more crystallization steps must be employed in order to obtain a substantially pure product.

Another solution to this problem is reported in the US. Patent No. 2,215,398, to Karrer. The separation process disclosed here calls for the esterification of the epimers with an optically active acid such as 3-bromo-dca-mphor sulfonic acid. A disadvantage of this process is that optically active acids are usually expensive.

Consequently, there is a need for a process [for the resolution of 2 dl-a-tocopherol and esters thereof, which process avoids these disadvantages.

An object of this invention is to provide such a process.

A specific object of this invention is to provide a process for increasing the concentration of one of the epimers relative to the other of the epimers of 2dl-a-tocopherol and esters thereof.

Another specific object of this invention is to provide a process for separating the 2d epimer from the 21 epimer of 2dl-a-tocopherol and esters thereof, which process can be readily performed with relatively inexpensive materials with a minimum number of steps and with high yields.

These and other objects as may appear as this specification proceeds are achieved by this invention which is based upon the discovery that the 2d and 21 epimers of 2dl-rx-tocopherol, crystallizable esters of 2dl-a-tocopherol and certain optically inactive acids, and crystallizable salts of the acid succinate ester of 2dl-a-tocopherol have substantially different solubilities in solvents therefor and that they fractionally crystallize from solvent solutions thereof. In most cases the 2d epimer of these materials is less soluble in solvents therefor than the 21 epimer, wherefore, under crystallization conditions the 2d epimer tends to be concentrated in the insoluble fraction, particularly if the solutions are seeded with one or more crystals of the 2d epimer of the material involved. The only exception to this finding appears to be in the case of the 2d and 21 acid succinate esters, wherein the 21 epimer crystallizes preferentially.

In summary, this invention comprises a process for obtaining from epimeric material selected from a group of epimeric materials, hereinafter referred to as the specified group, a product wherein one epimer is at a weight ratio relative to the other epimer substantially greater than the weight ratio of said epimer to the other epimer in said epimeric material. The specified group consists of (1) mixtures of 2d-u-tocopherol and 21-!!- tocopherol, (2) epimeric mixtures of a crystallizable ester of Zd-ez-tOCOPhCI'Ol and an optically inactive acid, and a crystallizable ester of 2l-a-tocopherol and said acid, said acid being selected from the group consisting U of saturated aliphatic carboxylic acids having l24 carbon atoms, benzoic acid, p-phenylazobenzoic acid and succinic acid, and (3) epimeric mixtures of a crystallizable salt of a base and the acid succinate ester of ZCl-aof the process of this invention. This invention is not limited to these specific embodiments unless otherwise indicated.

Example 1 tocop 3 i a crystallizablfl salt of said base. and This example illustrates the isolation according to a the acid succinate ester of 2l-ix-tocopherol. Crystallizable Specific embodiment of a process of this invention of salts of h g Suicmate f i i g i i Zd-a-tocopheryl acetate from a 2dl-a-tocopheryl acetate are l q y t f neutra nation 0 t e an Succma e concentrate. It also illustrates the separation of 21 epimer esters with norganic and organic bases Examples of orfrom the concentrate according to a specific embodiment ganic bases include piperazine, morpholine, ethanolamine, of a process of this invention. and the like. The process comprises dissolving said material 102 grams of a zdl a tocopheryl acetate concentrate m a crystallizzitlon soivent therefor; changing made by reacting with pyridine as a catalyst 2dl-ix-tocoperature. of sald.solutlon to a g pherol (prepared as by condensing trimethylhydroqui- Substantial quantity of of Sald P 1S mso u none and natural phytol followed by distillation of the whereby crystaih ne.SOh dS are pre.clpltatad; pmfer' condensate in a molecular still) and acetic anhydride, gbly when lireclplt'fmon 1S substantlany.complete P and having a purity of about 98% is dissolved in 500 mg crysianme Solids i the reiultmg. mother q milliliters of ethanol at -25 C. The temperature of h sohds i Obtained. comprise one of send the resulting solution is changed to 20 C. and the eplmia'rs i an Increased welght relative to the other solution is held for 72 hours at this temperature. During of 52nd eplmers preferred embodlments i the Process 20 this period of time, crystalline solids precipitate from the i Step of c.hang1}1g the temperature also Includes solution. The crystalline solids are separated from the mg solution more crystals of the i f mother liquor by filtration and residual solvent removed of Increased i ratio m the Subsequently preclpl' therefrom at reduced pressure at 5 C. A typical quantity tated crystannie S 1 1 h 0- of the crystalline fraction thus obtained is 88.3 grams. The crystalhzatlon w 1S Typically, it is enriched in the 2d epimer, a typical Weight at the P F F mvolv.ed m the practice of thls ratio of the 2d epimer to the 21 epimer being 51:49. The q Whlch i Inert relanve i materials f thg crystalline fraction is dissolved in 440 milliliters of specliied group under the concimons Involved In the ethanol at 20-25 C. and the resulting solution is cooled practlce of this F pl Whlch one hemperature to 20 C. It is then seeded with crystals of 2d-a-tocodissolves Substannal quantmes Of 2 materials and at 39 pheryl acetate and the seeded solution held at this tema temperalure the .c.rystalhza.tlon temparature perature for 10 days. During this period of time crystalcrystallizes substantial quantities of said materials. The H n e 801i ds precipitaw The crystalline 801i d5 are filtered solvent can be one comliomid or a mnmire of Compounds from the mother liquor and residual solvent removed Examples of a crystallization solvent include methanol, therefrom under reduced ambient pressure at c A ethanol, acetone, isooctane, hexane, isopropanol, methyl typical quantity of crystalline 501i (18 thus obtaine is ethyl F g g ga esters dunethoxy ethane 39.9 grams and typically the crystalline solids have a acetonitri e, an t e i e. h This invention also comprises a process for separating 5 253E 35 l i igg g s zgz ioi g F one of the two epimers from the other of the two epimers p C p a e of material selected from the specified group. This process P Hons andfypfcal data Obtained reheatlng comprises repeating the foregoing procedure relative to this fr actional crystallization procedure (dissolving at the crystalline solids until a crystalline product is obcrystalllzlng at filieflng a tained which consists essentially of said one of the two lng Solvent y Vacuum at 5 are SummaflZed 11 t epimers substantially free of the other of the two epimers. following table:

Weight in Grams oi Weight in Grams of Specific Rotation Optical Purity (in Crystalliza- Volume in Milli- Crystz lline Solids Crystallization Crystalline Solids Value ([QJJ) of percent by weight) tion Step liters of Ethanol Dissolved Tune in Hours Obtained crystglitrgieniigids stiigsryosltjzzlgggd 33 3 ii? iii. 3i 2% i512 24 121 5 +31 11 5s 5s 12. 2 120 s. 9 +3. 20 100 The fractional crystallization procedure of this invention is useful in separating the 2d epimer from the 21 epimer in the chemical conversion of the 21 epimer to the 2d epimer under conditions wherein. an epimeric mixture is obtained. One process for effecting such a chemical conversion comprises the steps of oxidizing 21- lX-tOCOphBI'Ol. to the corresponding tocoquinone, reducing the Zl-a-tocoquinone to the corresponding hydroquinone and cyclizing the 2l-a-tocohydroq'uinone under conditions which result in the formation of the 2d epimer. These conditions are such that a substantial proportion of the 2l-a-tocohydroquinone is also converted to a substantial quantity of the 21 epimer. The resulting mixture of 2d and 21 epimers is fractionally crystallized according to this invention to separate therefrom the 2d epimer. The 21 epimer which remains is preferably recycled through the chemical conversion process.

This invention is further illustrated by the following working examples, which include specific embodiments The end product of crystalline solids typically has a melting point of 27-28 C. This and the typical specific rotation value thereof indicate it to be identical with cc-tOCO- pheryl acetate obtained from natural u-tocopherol. Furthermore, the crystalline product typically has the same biological potency as natural a-tocopheryl acetate as determined by the standard, rat anti-sterility assay.

The filtrates resulting from all the foregoing crystallization steps are combined. Part or all of the solvent is removed therefrom at reduced pressure at 5 C. It is not necessaiy to remove all of the solvent; enough is removed so that on substantial reduction of the solution temperature a substantial quantity of dissolved crystalline material will precipitate. However, for the purpose of demonstrating this embodiment of the invention, it is preferred to remove all of the solvent. In such case, the residue is a-tocopheryl acetate material, a typical quantity of which is 48 grams. It consists essentially of Zd-octoccpheryl acetate and 2l-a-tocopheryl acetate at a typical weight ratio of 40:60. This material is dissolved in 5 150 milliliters of ethanol. The resulting solution is cooled to 20" C. and the cooled solution is seeded with crystals of 2l-a-tocopheryl acetate. The seeded solution is then stored at 20 C. for twenty-four hours. During this Example 3 This example illustrates a specific embodiment of the process for converting 2l-u-tocopherol to 2d-a-tocopherol time, crystalline solids precipitate from the solution. The 5 employing a Specific embodiment of a fractional y crystalline solids are filtered to give a product rich in the lization procedure of this invention. 21 epimi A yp q y of the Product thus 4.87 grams of 2l-a-tocopherol having 100% purity by 'tained is 22 grams. A typical specific rotation ot the prodthe Emmgriegngel assay and having a typical li bnot is [0411) whlch l i lpunty sorption value of E(1%, 1 cm., isooctane) (292 me) of 7 Walght of t 21 eplmer' W =73.9 is oxidized with ferric chloride in a two-phase talhzation procedure is repeated four more times, the 1' t t at th d d quantities of solvent and solids dissolved, the crystalliza- Vsn em accor me 0 Proce ure an con Hons tion times, typical quantities of crystalline solids obtained, disclosed In the Patent 23563414, to Robeson specific rotation of the solids obtained and typical optical 6t The result 15 a Product Conslstlng essentlally 0f purities of the solids obtained are summarized in the 15 Zl-a-toCoquinone. A typical quantity of the product is following table.

Weight in Grams of Weight in Grams of Specific Rotation Optical Purity (in Crystalliza- Volume in Milli- Crystalline Solids Crystallization Crystalline Solids Value ([OJDW) of percent by weight) tion Step liters of Ethanol Dissolved Time in Hours Obtained Crystalline Solids of Crystalline Obtained Solids Obtained 110 i 22 72 10 1.67 92 50 10 72 6.8 -1.s9 96 33 6. 8 120 6. 0 1.94 97 l 6. 0 48 5. 3 2. 0 100 The specific rotation value of 2.0 of the product of the fifth crystallization step is not changed by further crystallization. The melting point of the fifth crystallization step product typically is 22-23 C. This product consists essentially of 2l-u-tocopheryl acetate.

Example 2 This example illustrates the preparation according to a specific embodiment of a process of this invention of a 2d-a-tocopherol concentrate from material comprising 2d-a-tocopherol and 2l-a-toc0pherol at a weight ratio of 78:22.

8.2 grams of material consisting essentially of 2-d-ixtocopherol and 2l-a-tocopherol at a weight ratio of 78:22 are dissolved in 75 milliliters of methanol and the resulting solution cooled to C. A seed crystal of 2d-atocopherol is added to the cooled solution and the seeded solution is held for 4 days at 20 C. During this time crystalline solids precipitate. The crystalline solids are separated from the, mother liquor at +5 C. The crystalline solids are allowed to melt and residual solvent is removed in vacuo at 20-25 C. The result is a Zd-rx-tOCO- pherol concentrate wherein the weight ratio of the 2d epimer to the 21 epimer is 94:6. A typical quantity of concentrate thus obtained is 4.0 grams.

Similar results are obtained in the case of ZdI-a-tocopheryl palmitate with the crystallization solvent being acetone at a volumetric ratio of solvent to the palmitate material of 20:1 and the temperature of crystallization being 5 C.; 2dl-a-tocopheryl benzoate when employing as the crystallization solvent ethanol at a volumetric ratio of 6:1 and a crystallization temperature of 20 C.; and 2dl-a-tocopheryl p-phenylazobenzoate wherein the crystallization solvent is isooctane at a volumetric ratio of 5:1 and the crystallization temperature is 5 C.

In the case of 2dl-u-tocopheryl acid succinate wherein the crystallization solvent is hexane at a volumetric ratio of solvent to the succinate ester of 15:1 and the crystalliz'ation temperature is 5 C., crystalline solids are obtained wherein the weight ratio of the 21 epimer to the 2d epimer is increased over that which prevailed before crystallization.

5.04 grams. A typical light absorption value is E(1%, 1 cm., isooctane) (269 mu) =409. A typical specific rotation value of the product is [a] =-1.64 (isooctane, c=10).

The 2l-a-tocoquinone product is dissolved in 55 milliliters of isopropyl ether in a separatory funnel and admixed with 2.5 grams of sodium hydrosulfite in 50 milliliters of water at 20-25 C. for 30 minutes. The aqueous phase is drawn off and discarded, and the residue is admixed three more times with fresh aqueous solutions of sodium hydrosulfite. The isopropyl ether solution which results is washed with three 20 milliliter portions of water, dried with anhydrous sodium sulfate, filtered, and diluted with an additional 55 milliliters of isopropyl ether.

5.0 grams of fused zinc chloride and 1.0 gram of zinc dust are added to the isopropyl ether solution and the resulting mixture refluxed for 24 hours on a steam bath. 2 milliliters of concentrated hydrochloric acid are added cautiously to the resulting reaction mixture and reflux is continued for another 4 hours. The mixture thus obtained is poured on ice, the ether layer separated, washed 3 times with water, dried with sodium sulfate, filtered and the isopropyl ether removed by distillation under vacuum. The product remaining consists essentially of 2d-ix-tocopherol and 2l-d-tocophero1.

The product is esterified by reacting it with acetic anhydride and pyridine as a catalyst. A typical quantity of the acetate ester product obtained is 5.5 grams, a typical light absorption value of the ester product is E(1%, 1 cm., ethanol) (283 m =42.1, and a typical specific rotation value is [u] =+l.81 (ethanol, c=10). From the specific rotation value, it is apparent that the weight ratio of the 2d epimer to the 21 epimer is 73:27.

The product is then subjected to fractional crystallization according to the process of this invention, each crystallization step being performed at 20" C., the number of crystallization steps, other conditions of crystallization and typical data being summarized in the following table:

Q the group consisting of saturated aliphatic carboxylic acids having 1-24 carbon atoms, benzoic acid, p-phenyl- Weight in Grams of Weight in Grams of Specific Rotation Optical Purity (in Clystalliza- Volume in Milli- Crystalline Solids CrystalliJzHation Crysaglline Sdolids \(I'Jaluet (g lfi g) percfercijtisyltiaigit) i T 0 rs ame rys a me 0 l s 0 ",1 tron Stop liters of Ethanol Dissolved one in u Obtained Solids obtained 'The crystalline product resulting from the fractional crystallization process consists essentially of 2d-u-tocopheryl acetate.

The filtrates from the crystallization steps are combined, solvent removed therefrom by evaporation under vacuum, the residue saponified by the procedure described in the National Formulary, eleventh edition, on page 378, and the conversion process repeated on the resulting 2l=a=tocopheral material either alone or with added 2l-o-tocopherol material. By such recycling in combination with the fractional crystallization process of this invention, 2l-e-tocopherol is converted to Zd-e-tocopherol.

Thus, there is provided a process for resolving Zdl-atocopherol, certain crystallizable esters thereof and crystallizable salts of the acid succinate ester thereof. In addition, there is provided a process for increasing the weight ratio of one of the epimers to the other of the epimers in a mixture of the epimers of ldl-a-tocopherol, certain crystallizable esters thereof and crystallizable salts of the acid succinate ester thereof.

Other features, advantages, and specific embodiments of this invention will be readily apparent to those in the exercise of ordinary skill in the art after reading the foregoing disclosures. In this connection, while specific embodiments of this invention have been described in considerable detail, variations and modifications of these embodiments can be effected without departing from the spirit and scope of the invention as disclosed and claimed.

I claim:

1. A process for obtaining from epimeric material selected from the group consisting of (1) mixtures of Zd-a-tocopherol and 2l-a-tocopherol, (2) epimeric mixtures of a crystallizable ester of 2d-a-tocopherol and an optically inactive acid, and a crystallizable ester of 21-0;- tocopherol and said acid, said acid being selected from the group consisting of saturated aliphatic carboxylic acids having 1-24 carbon atoms, benzoic acid, p-phenylazobenzoic acid and succinic acid, and (3) epimeric mixtures of a crystallizable salt of a base and the acid suc cinate ester of 2d-a-tocopherol, and a crystallizable salt of said base and the acid succinate ester of 21-or-t0- copherol, a product wherein one epimer is at a weight ratio relative to the other epimer substantially greater than the weight ratio of said one epimer to said other epimer in said epimeric material, which comprises: (1) dissolving said epimeric material in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which a substantial quantity of said epimeric material is insoluble in said solvent, whereby crystalline solids are precipitated from said solution; and (3) separating said solids from the resulting mother liquor, whereby said product is obtained.

2. A process according to claim 1 wherein said solids are said product.

3. A process for obtaining from epimeric material selected from the group consisting of (1) mixtures of 2d-a-tocopherol and 2l-e-t0copherol, (2) epimeric mixtures of a crystallizable ester of 2d-a-tocopherol and an optically inactive acid, and a crystallizable ester of 21-mtocopherol and said acid, said acid being selected from azobcnzoic acid and succinic acid, and (3) epimeric mixtures of a crystallizable salt of a base and the acid succinate ester of Zd-a-tocopherOl, and a crystallizable salt of said base and the acid succinate ester of 21-m-tocopherol, a product wherein one epimer is at a weight ratio relative to the other epimer substantially greater than the weight ratio of said one epimer to said other epimer in said epimeric material, which comprises: (1) dissolving said epimeric material in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which a substantial quantity of said epimeric material is insoluble in said solvent, and seeding said solution with a least one crystal of the epimer at the greater weight ratio relative to the other epimer in the crystalline solids subsequently precipitated from said solution, whereby crystalline solids are precipitated from said solutions; and (3) separating said solids from the resulting mother liquor, whereby said product is obtained.

4. A process according to claim 3 wherein said epimeric material consists essentially of 2dl-a-tocopheryl acetate and wherein said solids, which consist essentially of 2d-a-tocopheryl acetate at a weight ratio of Zl-oc-tO- copheryl acetate substantially greater than 1:1, are said product.

5. A process for separating an epimer from epimeric material selected from the group consisting of (1) mixtures of 2d-a-tocopherol and 2l-a-tocopherol, (2) epimeric mixtures of a crystallizable ester of 2d-a-tocopherol and an optically inactive acid, and a crystallizable ester of Zl-a-tOcopherol and said acid, said acid being selected from the group consisting of saturated aliphatic carboxylic acids having 1-24- carbon atoms, benzoic acid, p-phenylazobenzoic acid and succinic acid, and (3) epimeric mixtures of a crystallizable salt of a base and the acid succinate ester of Zd-nc-IIOCOphBIOl, and a crystallizable salt of said base and the acid succinate ester of 21-u-tocopherol, which comprises: (1) dissolving said epimeric material in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which a substantial quantity of said epimeric material is insoluble in said solvent, whereby crystalline solids are precipitated from said solution; (3) separating said solids from the resulting mother liquor, whereby a crystal fraction is obtained; (4) dissolving said crystal fraction in a crystallization solvent therefor; (5) repeating steps (2) and (3), whereby another crystal fraction is obtained; and (6) repeating steps (4) and (5) until a crystal fraction consisting essentially of said epimer substantially free of the other epimer is obtained.

6. A process for separating an epimer from epimeric material selected from the group consisting of (1) mixtures of 2d-a-tocopherol and 2l-a-tocopherol, (2) epimeric mixtures of a crystallizable ester of 2d-a-tocopherol and an optically inactive acid, and a crystallizable ester of ZI-OL-tOCOPheFO]. and said acid, said acid being selected from the group consisting of saturated aliphatic carboxylic acids having 1-24 carbon atoms, benzoic acid, pphenylazobenzoic acid and succinic acid, and (3) epimeric mixtures of a crystallizable salt of a base and the acid succinate ester of 2 d-a-tocopherol, and a crystalliz able salt of said base and the acid succinate ester of 2l-ot-tocopherol, which comprises: (1) dissolving said epimeric material in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which a substantial quantity of said epimeric material is insoluble in said solvent, and seeding said solution with at least one crystal of said epimer, whereby crystalline solids are precipitated from said solution; (3) separating said solids from the resulting mother liquor, whereby a crystal fraction is obtained; (4) dissolving said crystal fraction in a crystallization solvent therefor; (5) repeating steps (2) and (3), whereby another crystal fraction is obtained; and (6) repeating steps (4) and (5) until a crystal fraction consisting essentially of said epimer substantially free of the other epimer is obtained.

7. A process according to claim 6 wherein said epimeric material consists essentially of 2dl-ot-tocopherol acetate and said epimer is Zd-a-acetate.

8. A process according to claim 7 wherein said crystallization solvent consists essentially of ethanol and step (2) is carried out by cooling said solution.

9. A process according to claim 6 wherein (a) the mother liquors are combined, (b) the solvent content is adjusted so that on changing the solution temperature to a crystallization temperature Whereat the material dissolved by said solvent is less soluble therein a substantial quantity of crystalline solids will precipitate, (c) the solution temperature is changed to said crystallization temperature and at least one crystal of said other epimer is added, whereby crystalline solids are precipitated, (d) said solids are separated from the resulting mother liquor, whereby a crystal fraction is obtained, (e) said crystal fraction is dissolved in a crystallization solvent therefor, (f) steps (c) and (d) are repeated whereby another crystal fraction is obtained, and steps (e) and (f) are repeated until a crystal fraction consisting essentially of said other epimer substantially free of said epimer is obtained.

10. In a process for converting 2l-u-tocopherol to 2du-tocopherol, wherein a mixture of 2d-ot-tocopherol and 2l-a-tocopherol is obtained, the steps of (1) dissolving said mixture in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which at least a substantial portion of the mixture is insoluble in said solvent, whereby crystalline solids are precipitated from said solution; (3) separating said solids from the resulting mother liquor, whereby a crystal fraction is obtained; (4) dissolving said crystal fraction in a crystallization solvent therefor; (5) repeating steps (2) and (3) whereby another crystal fraction is obtained; and (6) repeating steps (4) and (5) until a crystal fraction consisting essentially of 2d-a-tocopherol of the desired degree of purity is obtained.

11. In a process for converting Zl-OL-tOCOPheI'Ol. to 2dot-tocopherol, wherein the 21 epimer is redduced to 21-0;- tocohydroquinone and the 2l-a-tocohydroquinone is cyclized under conditions which yield a mixture of the 2d and 21 epimers, the steps of (l) dissolving said mixture in a crystallization solvent therefor, whereby a solution is formed; (2) changing the temperature of said solution to a temperature at which at least a substantial portion of the mixture is insoluble in said solvent, whereby crystalline solids are precipitated from said solution; (3) separating said solids from the resulting mother liquor, whereby a crystal fraction is obtained; (4) dissolving said crystal fraction in a crystallization solvent therefor; (5) repeating steps (2) and (3) whereby another crystal fraction is obtained; and (6) repeating steps (4) and (5) until a crystal fraction consisting essentially of 2d-0L-tOOO- pherol of the desired degree of purity is obtained.

12. A process according to claim 11 wherein said final crystal fraction is substantially free of 2l-a-tocopherol.

13. A process according to claim lll wherein 2l-oz-t0c0- pherol is separated from the mother liquors and recycled.

References Cited UNITED STATES PATENTS 2,215,398 9/1940 Karrer 260341.5 3,153,053 10/1964 Robeson et al. 260-345.6

WALTER A. MODANCE, Primary Examiner. JOHN M. FORD, Assistant Examiner. 

1. A PROCESS FOR OBTAINING FROM EPIMERIC MATERIAL SELECTED FROM THE GROUP CONSISTING OF (1) MIXTURES OF 2D-A-TOCOPHEROL AND 21-A-TOCOPHEROL, (2) EPIMERIC MIXTURES OF A CRYSTALLIZABLE ESTER OF 2D-A-TOCOPHEROL AND AN OPTICALLY INACTIVE ACID, AND A CRYSTALLIZABLE ESTER OF 21-ATOCOPHEROL AND SAID ACID, SAID ACID BEING SELECTED FROM THE GROUP CONSISTING OF SATURATED ALIPHATIC CARBOXYLIC ACIDS HAVING 1-24 CARBON ATOMS, BENZOIC ACID, P-PHENYLAZOBENZOIC ACID AND SUCCINIC ACID, AND (3) EPIMERIC MIXTURES OF A CRYSTALLIZABLE SALT OF A BASE AND THE ACID SUCCINATE ESTER OF 2D-A-TOCOPHEROL, AND A CRYSTALLIZABLE SALT OF SAID BASE AND THE ACID SUCCINATE ESTER OF 21-A-TOCOPHEROL, A PRODUCT WHEREIN ONE EPIMER IS AT A WEIGHT RATION RELATIVE TO THE OUTER EPIMER SUBSTANTIALLY GREATER THAN THE WEIGHT RATIO OF SAID ONE EPIMER TO SAID OTHER EPIMER IN SAID EPIMERIC MATERIAL, WHICH COMPRISES: (1) DISSOLVING SAID EPIMERIC MATERIAL IN A CRYSTALLIZATION SOLVENT THEREFOR, WHEREBY A SOLUTION IS FORMED; (2) CHANGING THE TEMPERATURE OF SAID SOLUTION TO A TEMPERATURE AT WHICH A SUBSTANTIAL QUANTITY OF SAID EPIMERIC MATERIAL IS INSOLUBLE IN SAID SOLVENT, WHEREBY CRYSTALLINE SOLIDS ARE PRECIPITATED FROM SAID SOLUTION; AND (3) SEPARATING SAID SOLIDS FROM THE RESULTING MOTHER LIQUOR, WHEREBY SAID PRODUCT IS OBTAINED. 